CHARACTERIZATION of CLINICALLY SIGNIFICANT BREAKTHROUGH HEMOLYSIS in PATIENTS with PAROXYSMAL NOCTURNAL HEMOGLOBINURIA TREATED with PEGCETACOPLAN.
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All Authors
De Latour, R.P.
De Castro, C.
Mulherin, B.
Patriquin, C.J.
Selvaratnam, V.
Kelly, R.J.
Griffin, M.
Surova, E.
Szamosi, J.
Uchendu, U.
LTHT Author
Kelly, Richard
Griffin, Morag
Griffin, Morag
LTHT Department
Oncology
Haematology
Haematology
Non Medic
Publication Date
2024
Item Type
Conference Abstract
Language
Subject
ADULT , DRUG-RELATED SIDE EFFECTS AND ADVERSE REACTIONS , ANAEMIA , CONTROLLED CLINICAL TRIALS AS TOPIC , DRUG THERAPY , WOMEN , FOLLOW-UP-STUDIES , INCIDENCE , MEN , HAEMOGLOBINURIA , CLINICAL TRIALS AS TOPIC , VACCINATION , HAEMOGLOBINS
Subject Headings
Abstract
Background: Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by complement-mediated hemolysis and increased risk of thrombosis. Pegcetacoplan (PEG) is the first complement C3 inhibitor approved by the EMA/FDA for the treatment of adults with PNH, and targets both intravascular and extravascular hemolysis. All patients with PNH on complement inhibitor therapy are at risk of breakthrough hemolysis of varying severity, which in some cases can be triggered by complement-amplifying conditions (CACs) such as infection or vaccination. Emerging evidence suggests breakthrough hemolysis on PEG can be effectively managed by intensive PEG dosing (Griffin et al. Blood 2022). The integrated analysis of data from 2 pivotal PEG trials (PEGASUS NCT03500549; PRINCE NCT04085601) and the subsequent open-label extension (OLE) APL2-307 study (NCT03531255) aimed to evaluate the long-term efficacy and safety of PEG for PNH patients. Here, we provide a definition for clinically significant breakthrough hemolysis (cs-BTH) events and examine their occurrence across the 3 PEG trials. Aim(s): Characterize cs-BTH events during PEG treatment in terms of incidence, duration, potential concomitant CACs, and management strategies. Method(s): A safety baseline was used in this integrated analysis, defined as time of initiation of PEG monotherapy in the 2 pivotal PEG trials. Patients initially received PEG 1080 mg subcutaneously twice weekly but dose escalations to once every 3 days or 3 times weekly were permitted. An event of cs-BTH was defined as an adverse event (AE) report of hemolysis by investigators in the presence of all the following: lactate dehydrogenase (LDH) >2x upper limit of normal (ULN), prior LDH <1.5x ULN, and a decline in hemoglobin (Hb) by >=2 g/dL from a patient's prior median Hb. Events of cs-BTH were evaluated from safety baseline up to Weeks 132 (2.5 years PRINCE) and 156 (3 years PEGASUS). Result(s): As of data cutoff (31/1/2023), 37/132 patients had experienced cs-BTH, of whom 34 entered and were followed through the OLE study. Of the 34 patients, 10 have data available until their enrollment into an intensive PEG dosing substudy. Four patients switched to commercial PEG. Four patients withdrew due to AEs. Overall, there were 62 cs-BTH events in the 37 patients. Thirty-two (51.6%) were reported as severe, 25 (40.3%) as moderate, and 5 (8.1%) as mild hemolysis AEs. 24/37 (64.9%) patients experienced only 1 hemolysis event. Median duration of the reported hemolysis AEs was 26 days. The exposure-adjusted incidence was 0.19 events/year. Events of cs-BTH were characterized by a mean (standard deviation) Hb decrease of 4.4 (1.7) g/dL compared to subjects' median, and median (interquartile range) LDH during the events reached 1850 (464, 5055) U/L (ULN: 226 U/L). A potential CAC was associated with 21/62 (33.9%) cs-BTH events. Vaccination or infection preceded 5 and 16 cs-BTH events, respectively. Packed red blood cell (PRBC) transfusions were administered during 33 (53.2%) cs-BTH events to manage the subsequent anemia, with an average of 1.5 units used per transfusion. Five patients in 6 cs-BTH (9.7%) events received rescue complement C5 inhibitor (C5i). Conclusion(s): Among patients with PNH treated with PEG in 2 pivotal Phase 3 clinical trials and a follow-up long-term OLE study, the exposure-adjusted incidence of cs-BTH was 0.19 events/year and considered infrequent. Around half of the hemolysis events were reported as mild or moderate. During cs-BTH events, pronounced declines in Hb were managed with PRBC transfusions and C5i in 33 and 6 of 62 cases, respectively.
Journal
HemaSphere